Small subcortical strokes (S3) also known as lacunar strokes, are a common stroke subtype accounting for at least 25% of all ischemic strokes. In Hispanic Americans, S3 are a frequent stroke subtype and occur at a relatively young age. S3 are usually due to small vessel disease, a common substrate for vascular dementia. Over two million survivors of S3 are at risk for recurrent stroke and for vascular dementia; millions more suffer sub-clinical S3 and cognitive decline caused by small vessel disease. Secondary Prevention of Small Subcortical Strokes (SPS3) is an international randomized, multicentre clinical trial testing two interventions in a factorial design. It will enroll 3000 participants (20% of whom will be Hispanic Americans) with symptomatic, MRI-defined S3 without carotid stenosis or major cardio-embolic sources. Patients are assigned, in a factorial design, to two interventions: 1. Antiplatelet Intervention: 325 mg/d vs. aspirin 325 mg/d plus clopidogrel 75 mg/d. 2. Blood Pressure Invention: systolic blood pressure targets of 130 to 149 mmHg vs. <130 mmHg. The antiplatelet comparison is double-blinded, while the blood pressure intervention is open- label with blinded assessment and verification of clinical events. Follow-up is every three months for a mean of 3 years. Main study outcomes are: 1) recurrent stroke (ischemic and hemorrhagic), 2) cognitive decline, 3) major vascular events The key hypotheses for SPS3 are: 1. Combination antiplatelet therapy is more efficacious than aspirin alone for prevention of stroke recurrence and for reduction in cognitive decline. 2. Intensive blood pressure control is associated with fewer recurrent strokes and reduction in cognitive decline. 3. The absolute reduction in stroke and cognitive decline will be greater in Hispanic Americans vs. non-Hispanic white participants. As of November 1, 2010, 2865 patients were enrolled in 66 currently active clinical sites. No previous randomized trials have focused specifically on secondary prevention of stroke after S3, on optimal target levels of blood pressure control after stroke and their relationship to cognitive decline, or on prevention of stroke and dementia in Hispanic Americans. The results of SPS3 will likely lead to important reductions in the burden of serious neurological diseases (stroke and vascular dementia) for millions of people with S3, and particularly for Hispanic Americans. The study objectives remain unchanged from the original application. The purpose of this application is to request support for continuation and completion of the trial necessitated by the increase in sample size of 500 participants and an additional year of follow up for all subjects in order to accrue the required number of primary events. PUBLIC HEALTH RELEVANCE: At least 200,000 small subcortical strokes (S3) occur annually in the U.S., with nearly two million S3 survivors at high risk for recurrent stroke and vascular dementia. It remains unclear how to optimally prevent stroke recurrence and cognitive impairment in this population. SPS3 will address several important clinical and scientific questions by testing two interventions in patients with recent MRI-defined S3. The results will inform the management of millions of patients with this common vascular disorder.